Familial follicular cell thyroid carcinomas in a large number of Dutch German longhaired pointers

Yu, Yun; Krupa, A.; Keesler, Rebekah I.; Grinwis, Guy C. M.; Ruijsscher, M.; Vos, Johan de; Groenen, M.A.M.; Crooijmans, R.P.M.A.

doi:10.1111/vco.12769

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…Although the inbreeding level in Dutch GLPs is relatively low in comparison to other 11 pointer setter breeds according to the current study, inbreeding level in certain subpopulations of GLPs is high and this probably contributes to the high incidence of follicular cell thyroid carcinoma. (Yu et al, 2021 , 2022 ). To eradicate genetic defects from GLPs, inbreeding control is essential.…”

Section: Discussionmentioning

confidence: 98%

“…Besides the popularity of GLP in Germany, breeding GLPs is also popular in the Netherlands. The Dutch population of GLP was found to be predisposed to a genetic form of follicular cell thyroid carcinoma (FCC) (Yu et al, 2022 ). Inbreeding analysis based on both pedigree and SNP array genotype data indicated that inbreeding contributed to the high incidence of the genetic FCC in the population (Yu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Unique genetic signature and selection footprints in Dutch population of German Longhaired Pointer dogs

Liu

Windig

et al. 2022

Animal Genetics

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The German Longhaired Pointer (GLP) breed is a versatile pointer dog breed.In the current study, we investigated the genetic diversity of these dogs based on SNP array data and compared it to 11 other pointer setter breeds. The results show that GLPs have a relatively low level of inbreeding among these pointer breeds. In addition, with the availability of pedigree information of the GLPs, we demonstrate that the correlation between pedigree-based inbreeding and genotype-based inbreeding coefficients was high (R = 0.89 and 0.85). By investigating population structure between these 12 pointer setter breeds we showed that GLP is a breed distinct from other pointers and shares common ancestry with a few other pointing breeds. Finally, we identified selection signatures in GLPs using the runs of homozygosity islands method. The most significant runs of homozygosity island was detected on chromosome 30 harboring the genes RYR3, FMN1, and GREM1. The RYR3 gene plays a role in skeletal muscle contraction while the FMN1 and GREM1 genes are involved in limb development. The selection on these three genes could have contributed to the excellent athletic performance of GLPs, which is an extremely important characteristic for this hunting dog.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Unique genetic signature and selection footprints in Dutch population of German Longhaired Pointer dogs

Liu

Windig

et al. 2022

Animal Genetics

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“…We selected 7 GLPs affected by familial FCC from the dataset described previously, and inclusion in this study was approved by the owners [ 1 ]. Tumor tissues and blood samples were collected during the surgery or necropsy.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported familial thyroid follicular cell carcinomas (FCCs) in 54 Dutch German longhaired pointers (GLPs), identified by histological examination and an additional 29 dogs were suspected to be affected based on typical clinical signs [ 1 ]. The familial FCC was heterogeneous with 5 different histological subtypes: follicular thyroid carcinoma (FTC), papillary thyroid carcinoma (PTC), compact thyroid carcinoma (CTC), follicular-compact thyroid carcinoma (FCTC), and carcinosarcoma.…”

Section: Introductionmentioning

confidence: 99%

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

Manders

Grinwis

et al. 2022

BMC Genomics

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Background We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale. Results Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs’ tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified. Conclusion This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

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Familial follicular cell thyroid carcinomas in a large number of Dutch German longhaired pointers

Krupa

Keesler

et al. 2021

Vet Comparative Oncology

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Thyroid carcinomas (TCs) originating from follicular cells of the thyroid gland occur in both humans and dogs, and they have highly similar histomorphologic patterns. In dogs, TCs have not been extensively investigated, especially concerning the familial origin of TCs. Here, we report familial thyroid follicular cell carcinomas (FCCs) confirmed by histology in 54 Dutch origin German longhaired pointers. From the pedigree, 45 of 54 histopathologically confirmed cases are closely related to a pair of first-half cousins in the past, indicating a familial disease. In addition, genetics contributed more to the thyroid FCC than other factors by an estimated heritability of 0.62 based on pedigree.The age of diagnosis ranged between 4.5 and 13.5 years, and 76% of cases were diagnosed before 10 years of age, implying an early onset of disease. We observed a significant higher pedigree-based inbreeding coefficient in the affected dogs (mean F, 0.23) compared to unaffected dogs (mean F, 0.14), suggesting the contribution of inbreeding to tumour development. The unique occurrence of familial thyroid FCC in this dog population and the large number of affected dogs make this population an important model to identify the genetic basis of familial thyroid FCC in this breed and may contribute to the research into pathogenesis, prevention and treatment in humans.

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Familial follicular cell thyroid carcinomas in a large number of Dutch German longhaired pointers

Cited by 5 publications

References 24 publications

Unique genetic signature and selection footprints in Dutch population of German Longhaired Pointer dogs

Unique genetic signature and selection footprints in Dutch population of German Longhaired Pointer dogs

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

Familial follicular cell thyroid carcinomas in a large number of Dutch German longhaired pointers

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